In this revised application, we will investigate how the FK506 binding protein 5 (FKBP5) is up- regulated to coordinate how the brain responds to stress. Since 2004, our team has worked to show that single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased risk of psychopathologies caused by stress, as highlighted in Nature Genetics 36:1319-25 2004 & JAMA 299:1291-305 2008. We have also shown that these risk SNPs increase the levels of FKBP5 through a mechanism that involves demethylation of the FKBP5 gene (Nature Neuroscience. 16:33-41 2013 & Journal of Clinical Investigation 123:4158-69 2013). There are currently 2 other mechanisms besides these SNPs that are known to increase FKBP5 levels in the brain: 1) Stimulation of the glucocorticoid receptor (GR) by the steroid hormone cortisol (corticosterone/CORT), and 2) modulation of the receptor tyrosine kinase EphB2 (Attwood et al. Nature 473:372-5 2011). In our previous work, we found that mice lacking the FKBP5 gene (FKBP5-/- mice) are protected from stress-induced depressive-like phenotypes, and that apart from this improved resiliency, these mice seem very normal. Acute suppression of FKBP5 in the amygdala has also been shown to protect mice from anxiety-like behavior, but there are still gaps in our knowledge about the function and regulation of FKBP5 in the brain. While we know that FKBP5 does reduce resiliency to stress, we do not know whether chronically increased FKBP5 levels in the brain can fully model impaired stress resiliency through a mechanism that is similar to humans carrying risk SNPs. We also do not know how FKBP5 overexpression impacts learning and memory despite clear connections between stress and cognitive function. We know that chronic stress disrupts cognitive processes and electrophysiological function of neurons. But we do not know if stress- induced deficits in cognition, plasticity, hippocampal volume or neurogenesis are mediated by FKBP5. Lastly, we know that FKBP5 expression is up-regulated by GR and EphB2 signaling, and we also know that demethylation of the FKBP5 gene in humans contributes to FKBP5 upregulation. But we do not know how other epigenetic modifying proteins contribute to FKBP5 expression and demethylation, nor do we know how the EphB2 receptor regulates FKBP5 expression through a similar methylation mechanism. To fill these gaps, we will examine the effects of FKBP5 overexpression on stress resiliency and cognitive function, examine the effects of FKBP5 on cognitive and neuronal deficits caused by chronic stress and investigate the mechanisms that control FKBP5 expression. We anticipate that these studies will show the importance of FKBP5 to the brain's stress response, leading to new insights about its role in psychopathologies and cognitive function. We will also define new upstream regulators of FKBP5 expression.